Genomic instability in the naturally and prematurely aged myocardium

Federica de Majo, Leonie Martens, Jana Charlotte Hegenbarth, Frank Rühle, Magda R. Hamczyk, Rosa M. Nevado, Vicente Andrés, Erika Hilbold, Christian Bär, Thomas Thum, Martine de Boer, Dirk J. Duncker, Blanche Schroen, Anne Sophie Armand, Monika Stoll, Leon J. de Windt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)


Genomic instability, the unresolved accumulation of DNA variants,
is hypothesized as one of the contributors to the natural aging
process. We assessed the frequency of unresolved DNA damage
reaching the transcriptome of the murine myocardium during the
course of natural aging and in hearts from four distinct mouse
models of premature aging with established aging-related cardiac
dysfunctions. RNA sequencing and variant calling based on total
RNA sequencing was compared between hearts from naturally
aging mice, mice with cardiomyocyte-specific deficiency of Ercc1,
a component of the DNA repair machinery, mice with reduced
mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson–
Gilford progeria syndrome (HGPS). Our results demonstrate that
no enrichment in variants is evident in the naturally aging murine
hearts until 2 y of age from the HGPS mouse model or mice with
reduced telomere lengths. In contrast, a dramatic accumulation of
variants was evident in Ercc1 cardiomyocyte-specific knockout
mice with deficient DNA repair machinery, in mice with reduced
mitochondrial antioxidant capacity, and in the intestine, liver, and
lung of naturally aging mice. Our data demonstrate that genomic
instability does not evidently contribute to naturally aging of the
mouse heart in contrast to other organs and support the contention
that the endogenous DNA repair machinery is remarkably active to
maintain genomic integrity in cardiac cells throughout life.
Original languageEnglish
Article numbere2022974118
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
Publication statusPublished - 7 Sept 2021

Bibliographical note

ACKNOWLEDGMENTS. F.D.M. is supported by HS-BAFTA and Kootstra
fellowships of Maastricht University and a CVON-ARENA-PRIME fellowship.
L.M. is supported by the fund Innovative Medical Research of the University
of Münster Medical School (RÜ121510). M.R.H. is supported by a Juan de la
Cierva contract from the Spanish Ministerio de Ciencia, Innovación y Universidades (IJC2019-040798-I). R.M.N. is the beneficiary of a predoctoral contract from the Spanish Ministerio de Educación, Cultura y Deporte (FPU16/
05027). V.A. is supported by the Spanish Ministerio de Ciencia e Innovación
(PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC16/
00091) as member of the ERA-CVD JCT2016 EXPERT Network (European
Union’s Horizon 2020 Framework Programme), with cofunding from the
European Regional Development Fund (“Una manera de hacer Europa”).
The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is
supported by the Ministry for Research, Science and Innovation (MICIN), the
ISCIII, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence.
C.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) (BA5631/
2-1). T.T. was supported by the European Research Council (ERC) Consolidator Grant LONGHEART, by ERA-CVD JCT2016 EXPERT, and the DFG (TH903/
22-1). D.J.D., M.S., and L.J.D.W. acknowledge support from the Dutch CardioVascular Initiative: the Netherlands Heart Foundation, Dutch Federation
of University Medical Centers, ZonMW, and the Royal Netherlands Academy
of Sciences (CVON-ARENA-PRIME, CVON-RACE-V, CVON-PREDICT-2). B.S. acknowledges funding by the Netherlands Heart Foundation (Dr. Dekker
2014T105 and CVON-SHE-PREDICTS-HF) and a VIDI Award 917.14.363 from
the Dutch Research Council (NWO). A.S.A. was funded by Association Française
contres les Myopathies (AFM 18802). F.D.M., T.T., and L.J.D.W. are supported
by ERA-CVD JCT2016 EXPERT. M.S. is funded by the DFG (RTG2220, Project
281125614) and Marie Skłodowska-Curie Grant Agreement 81371. L.J.D.W.
was further supported by ERC Consolidator Grant 311549 CALMIRS, a VICI
Award 918-156-47 from NWO and Marie Skłodowska-Curie Grant Agreements
813716 and 765274.


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